A developmental toxicity study of tretinoin administered topically and orally to pregnant Wistar rats.

BACKGROUND: Although it is well established that oral tretinoin produces embryofetal developmental toxicity in various laboratory animals, the toxic potential of topical tretinoin has not been clearly established. OBJECTIVE: This study of tretinoin administration to pregnant Wistar rats was conducted to determine whether topical tretinoin is associated with adverse effects on reproductive function or embryofetal growth and development and to compare outcomes with topical and oral tretinoin. METHODS: Topical and oral tretinoin (1 to 20 mg/kg and 1 to 10 mg/kg, respectively) or vehicles alone were administered on gestational days 6 through 16 and 15, respectively. RESULTS: Topical tretinoin: After topical treatment, dams receiving 10 mg/kg daily or greater had severe local and systemic toxicity prompting discontinuation of tretinoin. At doses of 2.5 mg/kg or greater, dam weight gain and food consumption were significantly less than those of control dams. Offspring of dams receiving 5 mg/kg weighed significantly less, and offspring of dams receiving 2.5 mg/kg or greater had a significantly greater occurrence of supernumerary ribs compared with control offspring. Oral tretinoin: After oral treatment, in the absence of maternal toxicity, significantly more offspring of dams receiving 5 mg/kg or greater had supernumerary ribs, and offspring of the 10 mg/kg treatment group had a greater incidence of cleft palate than had control offspring. CONCLUSION: The local and systemic maternal toxicity found in association with supernumerary ribs and low weights in the offspring at topical tretinoin doses of 2.5 and 5 mg/kg suggests that these developmental effects may be nonspecific or maternally mediated. Oral tretinoin at doses of 10 mg/kg, however, is clearly associated with embryofetal alterations in the Wistar rat.

A developmental toxicity study of tretinoin emollient cream (Renova) applied topically to New Zealand white rabbits.

BACKGROUND: Embryofetal developmental toxicity associated with oral administration of vitamin A analogs has led to concern about risks from topical application. OBJECTIVE: This study was conducted to evaluate the potential developmental toxicity of tretinoin emollient cream when applied to the skin of pregnant New Zealand white rabbits during organogenesis (gestational days 7 through 19). METHODS: Twenty rabbits each were randomly assigned to a control group (group I) or to receive vehicle (group II) or tretinoin emollient cream topically at dosages of 10 (0.05 mg/kg*, group III) or 100 (0.5 mg/kg*, group IV) times that used clinically in humans. Does and fetuses were examined for tretinoin-induced toxic effects, and maternal plasma tretinoin and metabolite levels were measured. RESULTS: The rate of abortion was increased significantly in does in group IV (p < or = 0.01) compared with the control group. Dosage-dependent increases in incidence and severity of skin reactions occurred in groups administered the vehicle and the two dosages of tretinoin. Does in groups III and IV had clinical and necropsy observations that were considered direct or indirect effects of tretinoin administration, persistent weight loss, and reduced feed consumption. Maternal endogenous plasma tretinoin levels were below the lower limit of quantitation of 5 ng/ml and were not significantly altered with treatment. Group IV had significantly reduced mean fetal body weight (p < or = 0.01) and a greater frequency of resorptions compared with group I. Although external, visceral, or skeletal alterations occurred at significantly greater levels in group III, they were unrelated to tretinoin administration because the fetal incidences were not dosage dependent, and the litter incidence did not significantly differ from the control group values. CONCLUSION: Maternally toxic dosages of tretinoin were associated with an increased incidence of abortions and resorptions and reduced fetal body weight, two end points of developmental toxicity. Consistent with the absence of detectable tretinoin plasma levels, however, no changes in fetal morphology were attributable to tretinoin administration. *The milligrams per kilogram dosage refers to the amount of active ingredient (tretinoin). The 0.05 mg/kg and 0.5 mg/kg groups were treated with 0.005% and 0.05% wt/wt tretinoin emollient cream formulation. The 0.05% tretinoin emollient cream is the Renova clinical formulation. The 10 and 100 times clinical multiples refer to Renova clinical multiples and are based on a 50 kg adult patient's applying 500 mg of 0.05% tretinoin emollient cream formulation daily to yield a clinical dosage of 0.005 mg/kg.

Cartilage-staining technique for the examination of unskinned fetal rat specimens previously processed with alizarin red S.

A novel staining technique has been devised that permits a cartilage examination of unskinned fetal rats that have been previously processed for skeletal examination with alizarin red S. The procedure consists of rinsing alizarin red S-stained specimens in distilled water and placing the specimens in a 3% acetic acid solution. A transfer of the stain from bone to adjacent cartilage occurs, producing purple-stained cartilaginous structures that can be differentiated from still-discernible bone structures.

Novel accessory skull bone in fetal rats after exposure to aspirin.

Aspirin was administered by oral gavage to 25 gravid Sprague-Dawley rats on gestation day 10, as a single dose of 500 mg/kg, in a concentration of 50 mg/ml. The aspirin was suspended in a mixture of 0.5% w/v hydroxypropylmethylcellulose (Methocel E-4M) and 0.1% w/v polysorbate 80 (Tween 80). A control group of 25 gravid rats was given 10 ml/kg/day of the suspending vehicle alone, by oral gavage, on gestation days 6 through 15. C-sections were performed on gestation day 20. Approximately two-thirds of the fetuses were processed for skeletal examination with Alizarin Red S; the remaining fetuses were placed in Bouin's solution. Examination of the fetal skeletal specimens from the aspirin-treated group revealed a 20% fetal (43% litter) incidence of an accessory skull bone, located between the nasal and frontal bones. This structure ranged in size from a small, barely discernible, circular ossification site (less than 0.5 mm) to a relatively large, bilobate bone (approximately 2 mm). This anomaly has not been previously reported in fetal rats.

The effect of oral castor oil on the disposition of methyprylon in intoxicated dogs.

Clinical observations indicate that large oral doses of castor oil are effective in reducing the time of coma resulting from acute intoxication with lipophilic drugs. It has been further suggested that the rate of removal of these drugs from the body is increased by castor oil. In order to investigate the effect of castor oil on the disposition of lipophilic drugs, five dogs were given toxic doses of methyprylon by intravenous infusion. Each dog was treated with a large oral dose of castor oil in a cross-over fashion. No significant difference was observed in the sleep times of the dogs treated with castor oil, or in the methyprylon pharmacokinetics compared to controls. It was concluded that castor oil does not affect the disposition of methyprylon.

Influence of cobalt (dietary), cobalamins, and inorganic cobalt salts on phenytoin- and cortisone-induced teratogenesis in mice.

Various cobalt-containing agents (cyanocobalamin, sodium cobaltinitrite, and cobaltous chloride), which formerly had been shown to prevent the onset of cleft palate in CF-1 mice injected with cortisone, were studied to determine whether they would afford similar protection against phenytoin. Phenytoin, however, failed to cause cleft palate in the mouse fetus when given to pregnant animals alone; and cortisone, on the contrary, induced this anomaly in the presence of the so-called cobalt antagonists as well as when administered in their absence. It is suggested from these results that high dietary intake of cobalt prevents cleft palate caused by phenytoin challenge and also negates the protective effects associated with the acute administration of cobalt compounds. Therefore, it is concluded that these well-known teratogens inhibit palatal closure in mice by different mechanisms.